Now Available: Final Rule for FDAAA 801 and NIH Policy on Clinical Trial Reporting

Effects of Febuxostat on Adipokines and Kidney Disease in Diabetic Chronic Kidney Disease

This study has been completed.
Sponsor:
Collaborator:
Takeda
Information provided by (Responsible Party):
Srinvasan Beddhu, University of Utah
ClinicalTrials.gov Identifier:
NCT01350388
First received: April 20, 2011
Last updated: August 9, 2016
Last verified: August 2016
  Purpose

Hyperuricemia is emerging as a risk factor for development of diabetes and metabolic syndrome. Recently, it was shown in in-vitro cell culture experiments that hyperuricemia induces redox-dependent signaling and oxidative stress in adipocytes. By targeting levels of uric acid with febuxostat it is hypothesized that the levels of oxidative stress in adipose tissue (obtained by fat biopsy) will decrease.

Primary aims of the study are to determine whether febuxostat therapy in overweight or obese, diabetic patients with stage 3 Chronic Kidney Disease (CKD) and high serum uric acid levels

  1. will affect adipose tissue concentrations of thiobarbituric acid reactive substance (TBARS), a marker of oxidative stress
  2. will affect adipose tissue expression and concentrations of adiponectin; and
  3. will affect urinary concentrations of transforming growth factor (TGF)- B1.

Condition Intervention
Chronic Kidney Disease
Diabetes
Drug: Febuxostat
Drug: Placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Effects of Febuxostat on Adipokines and Kidney Disease in Diabetic Chronic Kidney Disease

Resource links provided by NLM:


Further study details as provided by University of Utah:

Primary Outcome Measures:
  • Change in Thiobarbituric Acid Reactive Substance (TBARS) Concentration in Adipose Tissue From Baseline to 24 Weeks [ Time Frame: Baseline and 24 weeks ] [ Designated as safety issue: No ]
    The percent difference in thiobarbituric acid reactive substance (TBARS) concentration geometric mean values from baseline to 24 weeks was calculated for each arm

  • Change in Adiponectin Concentration in Adipose Tissue From Baseline to 24 Weeks [ Time Frame: Baseline and 24 weeks ] [ Designated as safety issue: No ]
    The percent difference in adiponectin concentration geometric mean values from baseline to 24 weeks was calculated for each arm

  • Change in Urinary Concentrations of Transforming Growth Factor-beta1 (TGF-beta1) From Baseline to 24 Weeks [ Time Frame: Baseline and 24 weeks ] [ Designated as safety issue: No ]
    The percent difference in TGF-beta1 concentration geometric mean values from baseline to 24 weeks was calculated for each arm


Secondary Outcome Measures:
  • Change in Tumor Necrosis Factor-α (TNF-α) Concentration in Plasma From Baseline to 24 Weeks [ Time Frame: Baseline and 24 weeks ] [ Designated as safety issue: No ]
    The percent difference in plasma TNF-α concentration geometric mean values from baseline to 24 weeks was calculated for each arm

  • Change in Interleukin-6 (IL-6) Concentration in Plasma From Baseline to 24 Weeks [ Time Frame: Baseline and 24 weeks ] [ Designated as safety issue: No ]
    The percent difference in plasma IL-6 concentration geometric mean values from baseline to 24 weeks was calculated for each arm

  • Change in High Sensitivity C-Reactive Protein (hsCRP) Concentration in Plasma From Baseline to 24 Weeks [ Time Frame: Baseline and 24 weeks ] [ Designated as safety issue: No ]
    The percent difference in plasma hsCRP concentration geometric mean values from baseline to 24 weeks was calculated for each arm


Enrollment: 80
Study Start Date: May 2011
Study Completion Date: December 2013
Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Febuxostat
80 mg/day of febuxostat for 24 weeks
Drug: Febuxostat
80 mg/day of febuxostat for 24 weeks
Other Name: Uloric
Placebo Comparator: Placebo
1 placebo tablet per day for 24 weeks
Drug: Placebo
1 placebo tablet per day for 24 weeks

Detailed Description:

Hyperuricemia is highly prevalent in the US population and commonly clusters with obesity and metabolic syndrome. It remains controversial whether this reflects an epiphenomenon or connotes a causal role of hyperuricemia in metabolic syndrome. If indeed hyperuricemia plays a causal role in metabolic syndrome, it would be expected that hyperuricemia will impact on the molecular signals that mediate the effects of adiposity on inflammation and insulin resistance.

Adipokines, the protein hormones produced by the adipocytes, serve as the signals for the effects of adipocytes on insulin resistance, dyslipidemia, hypertension, inflammation and atherosclerosis. Adipokines include tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), plasminogen activator inhibitor (PAI-1), leptin, angiotensinogen and adiponectin. In obesity, the production of TNF-α, IL-6, PAI-1, leptin and angiotensinogen increases whereas the production of adiponectin decreases. Increased expression of pro-inflammatory TNF-α and IL-6 and decreased expression of anti-inflammatory adiponectin by adipocytes results in insulin resistance and inflammation.

As oxidative stress in adipose tissue is considered to play a critical role in dysregulation of adipokines production in obesity and that hyperuricemia induces oxidative stress in adipocytes, it is hypothesized that hyperuricemia alters adipose tissue production of adipokines; therefore, febuxostat therapy will decrease hyperuricemia and thereby, have beneficial effects on adipokine production by adipose tissue; the favorable effects on adipokine production by febuxostat therapy will result in decrease in plasma levels of markers of inflammation; and as a result of the above, urinary markers of kidney disease will improve.

Chronic Kidney Disease (CKD) patients with type 2 diabetes will be studies because this population has a high prevalence of hyperuricemia and likely represents a target population which might benefit from reduction of uric acid levels.

This is a placebo-controlled, double-blinded, randomized controlled trial to examine the effects of uric acid lowering with oral febuxostat on adipokines and markers of inflammation.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age > 18 years
  • BMI > 25 kg/m2
  • type 2 diabetes
  • serum uric acid ≥ 5.5 mg/dl in men and ≥ 4.6 mg/dl in women
  • eGFR 30-60 mL/min/1.73m2

Exclusion Criteria:

  • History of gout
  • concurrent use of azathioprine, mercaptopurine, theophylline, allopurinol, thiazolidinediones or warfarin
  • concurrent use of metformin
  • current antibiotic therapy
  • pregnant women
  • prisoners
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01350388

Locations
United States, Utah
University of Utah
Salt Lake City, Utah, United States, 84112
Sponsors and Collaborators
University of Utah
Takeda
Investigators
Principal Investigator: Srinivasan Beddhu, MD University of Utah
  More Information

Responsible Party: Srinvasan Beddhu, Srinivasan Beddhu, MD Associate Professor of Medicine, University of Utah
ClinicalTrials.gov Identifier: NCT01350388     History of Changes
Other Study ID Numbers: IRB_00044016 
Study First Received: April 20, 2011
Results First Received: June 6, 2016
Last Updated: August 9, 2016
Health Authority: United States: Institutional Review Board

Keywords provided by University of Utah:
Chronic Kidney Disease
Diabetes
Febuxostat
Inflammation
Hyperuricemia

Additional relevant MeSH terms:
Kidney Diseases
Renal Insufficiency, Chronic
Urologic Diseases
Renal Insufficiency
Febuxostat
Gout Suppressants
Antirheumatic Agents

ClinicalTrials.gov processed this record on December 09, 2016